Process for making parahydroxy-metanitro-phenylarsenious acid



Patented Nov. 16, 1926.

UNITED STATES PATENT OFFICE.

IWAN OSTROMISLENSKY, OI LOCUST POINT, NEW JERSEY, ASSIGNOR TO OSTRO PROD- UCTS CORPORATION OF AMERICA, '01 JERSEY CITY, NEW JERSEY, A CORPORATION OF NEW JERSEY.

PROCESS FOR MAKING raannrnnoxx-mn'ranxrno-rnnnxnansnnrous ACID.

No Drawing.

NE; NH; H.C 0.0003

Application filed July 22, 1922. Serial No. 578,882.

production of nylarsenious aci of salvarsan.

According to the Process of Ehrlich and 'Bertheim for the production of salvarsan, there are six separate reactions with a relatively small yield (approximatel. on a la oratory scale) of the fina product.- The six reactions of the Ehrlich and Bertheim synthesis are as follows:

garahydroxy-metanitro-pheequivalent to the synthesis H.CO.CO OH --Q No. no, HOQAnAr-QOHJHCMEO H:- y E E H IV v VI The Ehrlich and Bertheim synthesis therefore requires comparatively large plant facilities and entails large expenditures for power, labor and a considerable variety of raw materials and in addition as mentioned produces a comparatively small yield.

The principal object of the present invention accordingly is to overcome difiiculties found in rior processes, such as the Ehrlich and Bert eim process and accordingly to produce a process having relatively few steps requiring comparatively small lant facilities and expenditures for power, abor and raw materials and which shall give a relatively high yield of finished product havin equal or greater therapeutic value than salvarsan and similar materials heretofore produced. Another object of the invention is to provide a simple, efiicient process for (purifying, if necessary, the prodalct obtaine Y i The invention accordingly broadly consists in a process which comprisesnitrating diazotized arsanilic acid and recovering arahydroxy-metanitro-phenylarsenious aci It also includes the purification, if necessary, of the material produced by the process.

Example 1.

The following is a preferred example of the process: To a mixture of 250 grams of dry arsanilic acid (or the corres onding quantity of moist arsanilic acid) an 275 cc. of nitric acid, specific gravity 1.3 and 750 cc. of water is added as a single mass 133 grams of sodiumvnitrite at room temperature. The mixture is shaken until brown fumes of nitric acid appears which usually occurs in about 2 to 3 minutes. The mixtureis then heated to about 60 C. The heating is then immediately stopped and an exothermic reaction occurs. Care should be taken during the course of this reaction that the temperature does not rise above approximately 70 G. Any rise in temperature above this point ma be stopped by the addition of pieces 0 'ice. After the exothermic reaction has taken place and the temperature of the mixture has dropped to about 1440 0., the reaction mixture is heated for 6 to 9 hrs. under a reflux condenser at a temperature near the boiling point. Upon cooling to room temperature the parahydroxy-metanitrophenylarsenious acid separates as a heavy ye low or reddish crystalline mass and is fi tered by suction usin a. Buchner funnel. It is washed on the unnel with 100 cc. of cold water. iDrying is accomplished in a dry oven in the presence of air if desired at 3070 C. The

NHg

It will be understood that the strength of the nitric acid employed may be varied as desired. Considerably weaker solutions of nitric acid may be used-but where such Weak solutions are used it is more convenient to reduce the amount of water ori inally used in the reaction mixture. A slig t excess of nitric acid-over the calculated quantity required for the reaction should be maintained in the reaction mixture, otherwise strongly colored products are produced with substantially smaller uantities of (parahydroxymetanitro-pheny arsenious aci That pgrtion of the nitric acid which is used to cause diazotization by liberation of nitrous acid from sodium nitrite may be replaced by other acids, if desired.

Other examples of the process included in the invention are as follows:

Ewample 2.

250 gms. of dry (or the correspondin quantity of moist) arsanilic acid are mixe with 750 cc. of water and 275 cc. of nitric acid specific gravity 1.3. A portion of the acid started with does not dissolve. The mixture is cooled by cold water occasionally by water and a small quantityo ice),whereyield is approximately 85% based on the weiilht of arsanilic acid taken.

T e diazotization and nitration it will be observed in accordance with the above example take place in the same solution. The reaction taking place in accordance with the above procedure ma be indicated as follows the starting dpoint eing aniline instead oi arsanilic aci 2 ----a ---e E0 AB A OEJHCLZH O aN Ha N Hg H upon it usually crystallizes out into a gruellike mass. The diazotization is performed by a solution of techanical sodium nitrite (i. e. the theoretical quantity of NaNO,) in 150 cc. of water at a temperature of l0-l8.

Diazotization is controlled by reactive starch otassium iodide paper. The temperature oi diazotization may fluctuate within 75 Wide limits. When all the nitrite has been added, the reaction mixture containing a small sediment is allowed to stand at a normal temperature from 30 minutes to 1 hour or more. The solution thus obtained is heated in a vessel of large ca acity such as a large flask or porcelain dis on a sand bath, using a free flame, until the complete decomposition of the diazo-nitrate is reached. The end of the reaction may be detected by the discontinuance of the evolution of bubbles of nitrogen and its oxides. If the conditions of the decomposition (temperature, evaporation surface of the vessel, etc.) hinder the evaporation, then the solution of the reaction products, after decomposition, is evaporate to about 900 cc. of the total volume.

The decomposed and concentrated solution of the products is allowed to stand for 16 hours at ordinary temperatures. The parahydroxy-metanitro-phenylarsenious acid which by this time has separated out in the form of a heavy yellow or reddish crystalline mass, is filterdd by suction. Washing 1 and drying are accomplished as in Example.

1. The yield is 200 ms, i. e.. 80% calculatefil on the weight 0 'arsanilic acid started wit Ewample .9.

A mixture of 500 gram arsanilic acid, 1500 cc. of water, 684 cc. of HNO, specific avity 1.3 is heated after its diazotization at 1225 gms. NaNO dissolved in 300 11 cc. of water) in a large porcelain cylinder to 70-80 by means of steam or a water bath for a period of 8-10 hours. The further manipulation of the reaction roduct is conducted as specified in Examp e No. 2. a

The yield reaches in this case 85%90 on the weight of the original arsanilic acid.

li'mamfle 4.

A solution of 250 gms. of arsanilic acid diazotized. according to conditions specified in Examples 2 or 3 is allowed to stand for several weeks at room temperature. Bubbles of molecular nitrogen are constantly evolved. The rate of decomposition is entirely determined by the temperature of the surroundin atmosphere. During the process of reaction the appearance and accumulation of parahydroxy-n1etanitro-phenylarsenious acid begins. The acid may be obtained either by the usual method of the evaporation of the solution (see above) or else by separating it in the cold in the form of the insoluble calcium salt. This will be described in the following examples.

For purification of the mass of parahydroxy-mctanitro-pheny]arsenious acid obtained in accordance with any one of the above procedures the following procedures may be carried out: (It will be noted that there may be obtained as by-products of the process orthonitrophenol, 2-4 dinitrophenol,

' and traces of various colored and tarry substances.

Example 1.

To 25 grams of crude but dried parahydroxy-metanitro-phenylarsenious acid or to the corresponding uantity of the moist acid thus obtained is brought to boiling, and a boiling solution of 33 guns. of calcium chloride in 50 cc. of water is added. The heating of the mixture to 100 is continued for lO- minutes. The calcium salt thus precipitated out (colored a are yellow) is squeezed in a press using a c oth ha and is then washed, while in the press, witii 500 cc. of hot water. The fairly well pressed salt thus obtained is mixed with 75 cc. of water, then shaken up and ce.of fuming hydrochloric acid specific gravity 1.19 are added. To the mixture are added about 2 gm's. of animal charcoal. The mixture is then boiled until com lete solution of'the free arsenious acid is' o tained.

It is then filtered.

The product which cixiystallizes out u on cooling may be found su ciently pure. his may be determined b the sodium hydrosulphite reaction (see escription above In this case the product is recrystallize once or twice from cc. of'a mixture of meth 1 alcohol and water (1 vol; 1 vol.) The yie d of the chemically pure parahydroxy-metanitro-phenylarsenious acid reaches in this case tiful golden-yellow needles which possess a light silky luster and are easily soluble in hot water. In cold water this salt is very slightly soluble.

Example 2.

100 "ms. of crude arahydroxy-metanitrohcnyfarsenious aci obtained as specified in Examples 2-4 are mixed with 150 cc. of cold water. To the mixture thus obtained 150 gms. of solid potassium h droxide are added. After the solution has been allowed to stand for about one hour, the small amount of yellow precipitate which has separated out meanwhile, is filtered off on a Buchncr funnel using mercerized cloth. The filtrate obtained is allowed to stand at ordinary temperature for 16 hours. The abundant precipitate which has separated out is carefully washed in a porcelain dish with 100 cc. of methyl alcohol. Then it is dissolved in 200 cc. of water. The solution is acidified, using 4Q cc. of fuming hydrochloric acid specific gravit 1.19, whereupon the precipitated chemically pure snow parahydroxy-metanitro-phenylarsenious acid which has precipitated out is filtered off and is dried as usual. The yield is about ms., i. e., 50%, calculating on the weight 0 the original acid.

The purification of the crude arahydroxymetanitro-phenylarsenious aci is most conveniently performed by means of its sodium salt. In this case some of the by-products of the reaction are also obtained in their pure sate.

Example 3.

500 gms. of crude but dried product obtained as specified in Examples 24 are dissolved in 1 liter of boiling 15%-16% solution of sodium h droxide. To the solution while still at a hell are added 500 cc. of ethyl alcohol (95%-98%). Then the heating of the solution is discontinued and into the still .hot mixture 500 co. more of'the same alcohol are introduced. Ethyl alcohol denatured by 5% of pure methyl alcohol may be used in this case. The mixture is allowed to stand for about 4 hours at ordinary temperatures. The reddish-orange crystals which have separated out are filtered on a Buchner funnel, pressed well and washed with 100 cc. of a mixture consisting of 50 cc. of the same ethyl alcoholand 50 cc. of water. Then they are pressed once more on the funnel.

The result obtained is a chemically pure crystalline disodium salt of parahydroxymetanitro-phen larsenious acid, which is colored orange an has a high index of refraction. This salt may be used for the prepawhite ration of salvarsau" without preliminary conversion into the free arsenious acid.

It is only necessary to filter the solution of this suit to free it from a slight turbidity and foreign matter, such as filter aper, fibres, dust, etc. The drying of the sa t may be conducted at ordinary ten'ipcratures, using a filter paper which in turn is placed on a cloth stretched over a frame. On heating, the moist salt easily becomes viscous, assuming an intense red coloration.

From the alcoholic filtrate which remains after the main mass of the disodium salt of parahydroxy-metanitro-phenylarsenious acid ias been separated out, 850 cc. are distilled over, the orthonitrophenol being carried over by vapors of water and alcohol. From the residue in the distilling flask, after about two hours at ordinary temperatures, the sodium salt of the dinitrophenol separates out The filtrate from the dinitrophenol is acidified with 100 cc. of fuming hydrochloric acid specific gravity 1.19. The, crystalline mass which thus se crates out is filtered oil on the following ay and is dried. This mass represents the crude parahydroxy-mctanitrophenylarsenious acid. The acid is easily purified according to the conditions specified in each of? the preceding examples. The yield of this product is gms. The total yield-of chemically pure parahydroxy-metanitro-phenylarsenious acid calculating the lisodinm salt as parahydroxy-mctanitro-phenylarsenious acid calculating the disodium salt as parahydroXy-metanitro-plienylarsenious acid is not less than 80%, calculated on the weight of the original crude product.

Each of the examples provides a product sufi'ieiently pure for conversion into salvarsan, The tests for such purity have been determined to be as follows:

The inventor has found that the color of water solutions of the alkali metal salt of chemically pure parahydroxy-metanitrophenylarsenions acids is in no egree intensified when acted upon by a minute quantity of sodium hydrosulphite (Na S OJ. An

intensification of color would prove, in full accordance with the tests of Ehrlich and Bertheim, the presence of dinitrohydroxyphenylarsenious acid or dinitrophenol.

The inventor has also observed that solutions of the alkali metal salt of the choral cally pure acid are almost instantaneously decolorizcd when exce's of sodium hydrosulphite {Nafijl} is added. Thus it has been shown that intensification of the color the shore solutions indicates the admixture of one impurity, whereas an increase of the time required for the ori inal color or" the solution to disappear indicates still another imgnn'ity. A solution of a sample not thoroughly purified may give no intensification of color when a minute quantity of sodium hydrosulphite is added, yet may decolorizc only very slowly when an excess is added-in other words, it may be free from dinitrohydroxy-phcnylarsenious acid and dinitrophcnol, and yet at the same time contain colored substances which are only slowly dccolorizcd by the Na S O Or conditions may be reversed-an intensification of color and an in'm'iediate loss of this color on addition of excess Na S O So SOdLllIIl hydrosulphite represents an excellent reagent for determining the purity of parahydroxy-mctanitro-phenylarscnious acid. It is that acid whose alkali metal salts 25 are instantaneously decolorized by sodium. hydrosulphite and do not give under the above mentioned conditions the slightest intensification of coloration which is preferably ured for the reduction into salvarsan. An acid which does not satisfy these conditions yields on reduction a preparation more toxic, possessing in addition an abnormal coloration, usually green The position of the side chains in the benzene nucleus of this nitrohydroxy-phenylarsenious acid has been definitely prevent 'lhere has been substituted for the arsenic group of the acid an atom of iodine, the sub stitution taking place with the aid of hydriodic acid (a mixture oi Kl and H 80 under ordinary conditions. During this substitution reaction an iodonitrophenol (80- 81) was isolated which has not yet been described in the literature. This substance separates out from other in the form of yellow prismatic needles; from hot waterin long, pale yellow needles. These at the beginning separate out in the form of 'oily drops producing an emulsion. The substance IS easily soluble in ether and alcohol, very little in cold, but somewhat more in hot water. It heated in a dry state it evolves vapors of free iodine. The potassium or sodium salt of this substance (ruby-red crystals) may be quickly separated from a water solution by the addition of solid alkali (KOH or NaOH).

The iodonitrophenol, isolated by the inventor under the same conditions from parahydroxy metanitro phenylarsenious acid when the latter was prepared by the method of Ehrlich and Bcrtheim. was found to be identical with the iodonitrophenol just mcntionell. l'ndeed, both preparations or a mixture ot the two melt at 80-8l C. Hence, this nitrohydroxy-phenylarsenious acid un doubtedly possesses the following structure:

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uietanit'ro-phenylarsenious acid obtained is the least expensive of any obtained by the various methods heretofore described. As compared with these methods for example Ehrlich and Bertheim method the yields obtained are considerably larger and the steps involved in carrying out the process are reduced approximately 50%. The plant facilitiesthus required for the production of the material are small as well as the-expenditures necessary for power, labor and raw materials. The variety of raw materials employed is also relatively small compared with prior processes.

As many apparently widely different embodiments of the invention may be made without departing from the spirit thereof, it will be understood that I do not intend to limit myself to the specific embodiment herein set forth except as indicated in the appended claims.

Having thus described my invention, what I claim and desire to protect by Letters Patent is:

1. A process of the kind described which comprises nitrating diazotized arsanilic acid, and recovering parahydroxy -metanitrophenylarsenious acid.

2. A process of the kind described which comprises diazotizing arsanilic acid, nitrating the diazotized arsanilic acid, and recov-' ering parahydroxy metanitro-phenylarsenious acid.

3. A process of the kind described which 5 comprises diazotizing arsanilic acid in the presence of water at a temperature below approximately 0., nitrating the diazotized arsanilic acid at a temperature below the boiling point of the mixture and recovering arahydroxy-metanitro-phenylarsemous aci 4. A process of the kind described which com rises nitrating diazotized arsanilic acid in t e presence of water at a temperature below t e boiling point of the reaction mixture, and recovering parahydroxy-meta:

nitrolphenylarsenious acid.

5. process of the kind described which comprises mixing arsanilic acid, nitrous acid and nitric acid, causing diazotization and nitration to occur in the same solution, and recovering parahydroxy-metanitro-phenylarsenious aci 6. A process of the kind described which comprises mixing arsanilic acid, nitrous acid and nitric acid, causin diazotization to occur at a temperature elow approximately 70 0. heating the mixture to a point just below its boiling point maintaining its temperature approximately at. such. point for SIX to mac hours, and recovering parahydroxy-metanitrohenylarsenious acid.

7. A process of t e kmd described which comprises preparin a mixture of arsanilic acid, mtnc acid an sodium nitrite for producing nitrous acid, heating the mixture to its boiling point, allowing an exothermic reaction to complete itself substantlally at a temperature below approximately 70 0.,

heating the mixture thus treated to a point 70 approximating its boiling point for SIX to nine hours,- and recovering (parahydroxymetanitro-phenylarsenious aci 8. A process of the kind described which comprises nitrating diazotized arsanilic acid, 7

acid, converting the (parahydroxy-metan'itrophenylarsenious aci into a salt, and recovering pure hydroxy-metanitro-phenylarsenious acid therefrom.

10. A process of the kind described which comprises diazotizing arsanilic acid in the presence of water at a temperature below approximately 70 0., nitrating the diazotizcd arsanilic acid at a temperature below the boilin point of the mixture adding an alkali, an recovering of (parahydroxy metanitro phenylarsenious aci 11. A processof the kind described which comprises diazoti'zing arsanilic acid in the presence of water approximately 7 0 0., nitrating the diazotized arsanilic acid at a temperature below the boiling point of the mixture, adding an alkali, recovering the alkali metal salt of (parahydroxy metanitro phenylarsenious aci and converting the alkali metal salt by addition of an acid into parahydroxy-metanitro-phenylarsenious acid.

12. A process of the kind described which comprises mixing arsanilic acid, nitrous acid and nitric acid, causin diazotization to occur at a temperature elow approximately 70 0., heating the mixture. to a point just below its boiling point maintaining its temperature approximatel six to nine hours, ad in to the reaction mixture so treated an alka i forming a soluble' alkali metal salt of arahydroxy-metanitro-phenylarsenious acid, converting this soluble alkali metal salt into insoluble salt, and recovering parahydroxy-metanitro-phenylarsenious aci 13. A process of the kind described which comprises mixing arsanilic acid, nitrous acid and nitric acid, causing diazotization to occur at a temperature below approximately 70 0., heating the mixture to a point just below its boiling point maintaining its temperature a proximatey at such point for six to nine ours, adding sodium hydroxide to the reaction mixture while boiling, adding ethyl alcohol to the mixture so treated,

se aratmg orange red crystals of the sodium sa t of Harahydroxy-metanitro phenylarsenious aci at such point ion.

the alkali metal salt at a temperature below 14. A process of the kind described which comprises treating parahydroxy-metanitrophenylarsenious acid and one or more of the followin imlpurities: orthonitrophenol, 2-4 dinitropiieno and traces of various colored and tarry substances, with an alkali, converting the parahydroxy-metanitro-phen larsenious acid into a salt, and mechanica 1y separating the salt from impurities.

15. A process of the kind described which comprises treating arahydroxy-metanitrophen larsenious acid and one or more of the ollowin impurities: orthonitrophenol, 2-4 dinitropl ienol and traces of various colored and tarry substances, with an alkali in solution, precipitating the salt of parahydroxy-metamtro-phenylarsenious acid as an insoluble precipitate, and filtering the salt to remove it from the solution containing the impurity.

16. A process of the kind described which comprises treating arahydroxy-metanitrophenylarsenious acid and one or more of memes the following impurities: orthonitro henol, h droxyphcnylarsenions acid, 2-4 initrophenol and traces of various colored and tarry substances, with sodium hydroxide in water solution, precipitating the sodium salt by1 ethyl alcohol, and recovering the sodium sa t.

17. A process of the kind described which comprises treating arahydroxy-metanitrophenylarsenious acid and one or-more of the following impurities: orthonitrophenol, hvdroxyphenylarsenious acid, 24= dinitrop enol and traces of various colored and tarry substances, with boiling alkali metal 11 droxide, adding an alcohol in which the alkali metal salt of parahydroxy-metanitrophenylarsenious acid is insoluble, and filtermg the alkali metal salt of parahydroxymetanitro-phenylarsenious acid which separates on standing.

Signed at New York, New York, this 21st day of July, 1922.

IWAN OSTROMISLENSKY. 

